DESCRIPTION (Applicant's Abstract): Obsessive Compulsive Disorder (OCD) is a chronic, debilitating condition. Despite recent treatment advances, approximately 10-30% of patients continue to suffer with severe OCD despite adequate trials of Clomipramine (CMI), selective serotonin reuptake inhibitors (SSRIs), pharmacological augmentation, and/or behavior therapy. To test whether IV CMI represented a safe and effective treatment alternative for "oral CMI refractory" patients, we conducted a double-blind placebo-controlled study. Our results indicate that IV CMI is a well-tolerated, safe mode of therapy and that it is significantly more effective than IV placebo for patients with a history of inadequate response to oral CMI. Additionally, the data suggest that the IV route leads to a more rapid response than the oral route, that the response rate increases with time (from 21% after infusion #14 to 43% one week later), and that the response is sustained and perhaps enhanced one month later. Despite these promising results, we cannot yet conclude that IV CMI is more effective or faster acting than oral CMI because we did not have a control group of patients concurrently treated with oral CMI. Further, our follow-up data was not collected in a double-blind fashion and the durability of response beyond one month was not ascertained. To address these issues, a definitive, controlled study is needed. In this proposed 4-year study, 88 OCD patients who failed to benefit adequately from oral CMI and at least one SSRI will be randomly assigned to receive 14 daily infusions of either IV CMI or IV placebo. During the infusion period, the IV CMI patients will also receive oral placebo while the IV placebo patients will also receive oral CMI. Oral and IV dosages start at 25 mg/day and increase to 250 mg/day using an identical dosing schedule. Outcome will be rated double-blind by an independent evaluator weekly for the first 8 weeks and at weeks 10 and 12. Responders at 10 weeks will be rated again in a double-blind fashion 3- and 6-months later. When completed, the study should provide an objective assessment of the efficacy of IV CMI over oral CMI for pharmacologically refractory OCD patients.